Sexually Transmitted Diseases:
An Increasing Proportion of Reported Chlamydia trachomatis Infections Are Repeated Diagnoses
Wikström, Erika MD*†; Bloigu, Aini B.Sci*; Öhman, Hanna MSci*; Hiltunen-Back, Eija MD, PhD*‡; Virtanen, Mikko J MSci*; Tasanen, Kaisa MD, PhD†; Paavonen, Jorma MD, PhD§; Lehtinen, Matti MD, PhD¶; Surcel, Heljä-Marja PhD*
From the *National Institute for Health and Welfare, Helsinki; †Department of Dermatology, University of Oulu, Oulu; ‡Department of Dermatology and Venereology, Helsinki University Hospital, Helsinki; §Department of Obstetrics and Gynecology, University of Helsinki, Helsinki; ¶School of Health Sciences, University of Tampere, Tampere, Finland
Supported by Helsinki and Oulu University Hospitals, The Finnish Society of Dermatology and Venereology, The Finnish Society Against Sexually Transmitted Diseases, and the EU-FP7 PREHDICT Network.
Correspondence: Heljä-Marja Surcel, PhD, National Institute for Health and Welfare, PO Box 310, 90101 Oulu, Finland. E-mail: email@example.com.
Received for publication May 8, 2012, and accepted August 9, 2012.
Background: In recent decades, increasing rates of Chlamydia cases have contrasted with decreasing Chlamydia trachomatis seroprevalence rates and decreasing Chlamydia-associated complication rates. We elucidated the conflicting trends by studying incidence of repeated Chlamydia infections over time.
Methods: Chlamydia cases reported during 1995 to 2009 were identified in the Finnish National Infectious Diseases Registry. Trends of single and repeated diagnoses of Chlamydia infection were analyzed.
Results: Our study population comprised 147,148 individuals with a total of 177,138 genital chlamydial infections. The proportion of annual repeated diagnoses of genital infections increased among female and males from 4.9% to 7.3% and from 3.8% to 5.3%, respectively. In 2009, 24.8% of the females and 20.3% of the males had had an earlier Chlamydia infection ever during the follow-up time. Of all the repeated diagnoses, 34.1% occurred within 12 months. The highest rates of repeated infection diagnoses occurred in 25-year-old women (37.0%) and in 29-year-old men (30.9%) in a cohort of individuals born in 1979.
Conclusions: A gradual increase of repeated Chlamydia infections resulted in 43% increase in annual infections between 1996 and 2009. The result is supportive of the existing seroprevalence data suggesting that Chlamydia infection burden is not increasing in the whole population. The increasing infection rates in males, in particular, justify development of effective strategy in preventing reinfections and onward transmission.
Chlamydia trachomatis is the most prevalent bacterial cause of sexually transmitted infection. Reported annual rates of C. trachomatis infection have been increasing in many European countries. Approximately half of the reported infections occur in 15- to 19-year-old adolescent females.1,2
Chlamydial infections in adolescents are of particular concern because of their asymptomatic characteristics and risk of long-term sequelae both in women and men.3,4 Since the middle of the 1990s, national programs have been implemented in many countries to reduce Chlamydia infection rates.5–7 In most countries, C. trachomatis infection rates increased in the late 1990s.8,9 This was partly due to transition to more sensitive testing methods (nucleic acid amplification tests [NAATs]), which facilitated screening. Infection rates have, however, remained high, and they are continuing to increase in many countries.10–13
We have previously reported increasing C. trachomatis infection occurrence from the 1990s to 2003.14,15 Simultaneously observed declining C. trachomatis seroprevalence, however, suggested that the true infection burden may have been decreasing.15 Comparable discrepancy between NAAT-reported cases and seroprevalence rates was reported in British Columbia and explained by the early treatment hypothesis, where improved diagnostics and subsequent early treatment were linked to an impaired immune response/undetectability of C. trachomatis antibodies.6 Impaired immunity might, in turn, expose individuals to repeated C. trachomatis infection and lead to increasing infection rates.
C. trachomatis infections often recur in young women8,16,17 via sexual risk-taking behavior18 or by transmission from the untreated partner.19 We wanted to determine impact of repeated and newly detected infections on increasing Chlamydia infection rates.
MATERIALS AND METHODS
In Finland, surveillance of sexually transmitted C. trachomatis infections has been based on mandatory notifications since 1987 by physicians and, since 1998, from laboratories only (during 1995–1997 from both) to the population-based National Infectious Diseases Register (NIDR). The study involved all registered C. trachomatis episodes, together with sufficient personal information in the NIDR from 1995 to 2009.8,11 According to nationwide instructions, a case was regarded as a new infection episode if the time interval between 2 laboratory-confirmed and laboratory-registered episodes in an individual was longer than 3 months. In association with a positive test result, each patient was provided with antibiotic treatment (mainly a single 1-g dose of azithromycin from the 1990s), which presumably was effective in infection clearance. No data on a test of cure, a treatment failure, or infections due to new exposure to the same or a different partner are available in the NIDR. The annual number of Chlamydia tests performed is not registered in the surveillance data. Testing for and treatment of C. trachomatis in general health care has been free of charge for the patients since 1987, in accordance with a Communicable Diseases Act and Decree (issued in 1986).
To analyze the occurrence of single and repeated C. trachomatis infection episodes in different age groups, the male and female study populations were divided into 3 age categories: younger than 23 years, 23 to 28 years, and older than 28 years, these being comparable with the age categories in our previous studies on the C. trachomatis seroprevalence.14,15 To further analyze possible trends in infection prevalence and proportion of repeated diagnoses, 3 comparable birth cohorts of younger than 23 years were formed both for females and males. The numbers of C. trachomatis infections were counted separately for each year for the period 1995 to 2009.
Laboratory Testing Methods During 1995 to 2009
According to the NIDR data, in 1995, 63% of patients with C. trachomatis were diagnosed by antigen detection tests, 16% by culture tests, and 21% by polymerase or ligase chain reaction tests. The proportion of NAAT methods in C. trachomatis diagnostics rapidly increased from 62% in 1997 (other methods: 27% by antigen detection tests and 11% by culture tests) to 95% in 2000 and 99.8% in 2002.
Ninety-five percent confidence intervals (95% CIs) were calculated by using a Confidence Interval Analysis program (Gardner & Altman 1989). Categorical variables were compared by χ2 tests, and χ2 tests were used for trend, as appropriate. Direct standardization was used to adjust for the effect of detection method (NAATs vs. other methods), applying distribution of the methods in each of the 3 separate cohorts to determine the relative weights. SPSS 18.0 for Windows (SPSS Inc, Chicago, IL) was used for data analysis.
In total, 177,138 C. trachomatis infection episodes in 147,148 individuals were registered in Finland in 1995 to 2009. During the same period, the study material included 29,990 (16.9 %) repeated infections characterized as a newly detected infections more than 3 months after a previous diagnoses. The incidence rate of C. trachomatis infection increased by 1.44-fold (95% confidence interval [CI], 1.40–1.49) when the number of diagnoses increased from 8030 cases in 1995 to 11,731 in 2000,8,11 and thereafter, it gradually (1.1-fold) in 2009. The increase in the number of Chlamydia diagnoses was more rapid in males than in females, especially among 15- to 19-year-old males (2.5-fold from 304 in 1995 to 767 in 2009). In 2009, 13,246 C. trachomatis cases were registered, more often in females (59%) than in males (41%).
Altogether, 16.2% (23,894/147,148) of the C. trachomatis–infected individuals had 2 or more infection episodes ever in 1995 to 2009, confirmed by positive laboratory test results. Most (65.3%) of the repeated infections were found in females (Fig. 1). A statistically significant difference in the proportions of repeated C. trachomatis infections between females and males (P < 0.001) was observed in all 3 age groups (<23, 23–28, and >28 years). In the 2 youngest age groups, the proportions of repeated diagnoses were greater among females, but among the group older than 28 years, the male proportional share of repeated diagnoses was greater (Fig. 1). Most females (80.2%; 12,509/15,588) and males (80.7%; 6703/8306) with repeated infections had only 2 episodes. During the whole follow-up time, of all the repeated infection diagnoses, 34.1% (10,227/29,990) occurred within 12 months.
Between 1996 and 2009, the proportion of annual repeated infections (a number of subjects who had been registered in the NIDR earlier within 12 months) increased from 4.9% to 7.3% (49% increase) in females and from 3.8% to 5.3% (39% increase) in males (Fig. 2). The increase was higher in adolescent females and young women (38% and 68%, respectively) than in the oldest age group (20%). Corresponding increases in males were 70%, 26%, and 23%, respectively. Overall, the proportion of registered cases who had had at least 1 Chlamydia infection episode earlier during the study period 1995 to 2009 increased considerably from 2002 to 2009 both in females (18% in 2002 and 24.8% in 2009, P < 0.001) and in males (14.8% and 20.3%, P < 0.001).
To further clarify the impact of reputed infections on the increasing infection rates, we evaluated the prevalences of primary and repeated diagnoses of C. trachomatis infection in 3 birth cohorts (1979–1981, 1982–1984, and 1985–1987) when the subjects were younger than 23 years. As shown in Table 1, the proportions of repeated diagnoses of C. trachomatis infections, adjusted for the diagnostic method (NAATs vs. other methods) increased significantly in females by 12% (from 17.4% to 19.5%) and in men by 26% (from 10.1% to 12.6%) during the follow-up period of 1995 to 2009 (both P values for trend, <0.001). At the same time, the corresponding increases in the prevalence of primary infections were 18% in females and 22% in males (Table 1). Separate analysis of the 1979 birth cohort (6080 women and 3752 men), who reached 16 years in 1995 and, owing to young age, presumably who had had only occasional Chlamydia infections before 1995, showed that the infection rates were highest at the ages of 20 and 23 years in females and males, respectively. In females, the proportion of proportion of repeated Chlamydia infection diagnoses peaked at the age of 25 years (37.0%) but remained high (32.9%) among women aged 26 to 30 years. In males, the repeated Chlamydia infection diagnoses peaked at the age of 29 years (30.9%; Fig. 3). No material differences in the distributions were noted in the separate analysis of 1982 and 1985 birth cohorts (data not shown).
In our population-based study, personal identifier-linked data concerning a total of 177,138 newly diagnosed C. trachomatis infections were available. Although the prevalence of Chlamydia infection showed a moderate increase in the birth cohorts (1979–1981, 1982–1984, and 1985–1987) when they were younger than 23 years, the rates of annual repeated infection diagnoses increased from 1995 to 2009 by 49% and 39% in women and men, respectively. In 2009, repeated infection diagnoses represented 25% and 20% of the registered episodes in women and men, supporting the role of repeated infections in the increasing C. trachomatis incidence rates.14 As previously reported,8 changing over to sensitive diagnostic tests from 1995 to 2000 only partly explains the increased infection incidence but not the differences observed in various age groups.8 A proportion of the increasing rate of repeated diagnoses could, however, be a result of more sensitive testing methods, although NAATs coverage has been almost 100% since 2002 in Finland.
The C. trachomatis infection rate is generally considered to be a reasonable approximation of prevalence20 and a reliable follow-up indicator of Chlamydia control programs. According to the results of recent studies by Satterwhite et al.,21,22 interpretation of trends in infection rates should include statistical adjustment for the proportion of NAATS. Controlling also for ethnicity or region, Satterwhite et al.22 reported a declining trend of Chlamydia prevalence despite apparently increasing incidence rates between 2004 and 2008 in the United States. The increasing proportion of infected adolescent females from 1995 to 20098,11 also suggest that the infection incidence rate as such is a confounded indicator of true infection burden in this population. Our C. trachomatis infection prevalence data and the earlier reported seroprevalence data15 in the same birth cohort of women (<23 years in 2001–2003; 10.0% vs. 9.2%) match well, which suggests that the use of seroprevalence data could be an alternative indicator of infection burden.
Although adolescent females had the highest amount of repeated infection diagnoses, a large increase of reported Chlamydia cases in males also impacts on C. trachomatis incidence rates. In the United States, a 46.6% increase in registered Chlamydia male cases was discovered between 1999 and 2004.23 There are no data available to evaluate whether these increasing rates reflect a true increase of infection burden in males or whether they are due to uptake of the sensitive NAAT techniques or a decreased threshold as regards participating in Chlamydia testing. Improved means of communication (text messages/e-mail) may also have improved contact tracing and resulted in increased testing in males.
Comparison of repeated infection rates in different studies is difficult because of different study populations, varying study settings, and, in particular, varying follow-up times ranging from a few months to several years.24–26 In general, registered rates of repeated Chlamydia infections have varied from 0% to 32%,17 suggesting that the rates of annual repeated infections in our study (7.3% in females and 5.3% in males) were low. It is noteworthy that individuals once tested positive are not retested on a regular basis and asymptomatic infections (whether repeated) remain undetected. The increased amount of repeated Chlamydia infection diagnoses is in line with increasing risk-taking behavior among adolescents (especially boys). Nowadays, sexual activity starts earlier than in the 1980s, the number of sex partners has increased, and the use of condoms has decreased.27,28 Our results in the 1979 birth cohort show that infection rates, most probably due to sexual risk taking behavior, increase up to 25 and 29 years in females and in males. Satterwhite et al.29 reported differing trends of Chlamydia infection in women and men. The proportion of repeated Chlamydia infections continue to increase or stay at a high level up to 30 years, suggesting that core groups continue sexual risk-taking behavior. A similar phenomenon has also been demonstrated in acquisition of high-risk human papillomavirus.30
Strengths of our study include the population-based material, a consistent reporting system, and personal identifiers, which enabled identification of repeated cases. A weakness of our study is a lack of data on the annual number of Chlamydia tests performed, but for example, in the Oulu University Hospital area in Northern Finland, the number of chlamydial polymerase chain reaction tests rose from 9158 to 13,392 from 2000 to 2010. During this period, the number of reported C. trachomatis cases remained stable in this hospital district,11 which indicates that the greater number of tests only partly explains the increasing Chlamydia rates overall. Available and systematic data on the test of cure would be needed to confirm the role of repeated infections in the increasing infection rates. Another limitation is in our study is the artificial period of more than 3 months between 2 registered C. trachomatis infection episodes and thus possible underestimation of the primary and repeated case rates. However, by using this time frame, it is assumed that we diminished the chance of possible cases of treatment failure being registered as new Chlamydia infections. We found that most of the registered infections occurred among young people (<23 years), but on the other hand, the cases with newly detected infections were older. More than 34% of the repeated diagnoses occurred within 12 months, which speaks for early retesting. In particular, males should be targeted because they serve as a reservoir for C. trachomatis.
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